Development of a controlled human infection model to study respiratory syncytial virus infection in older adults
Authors: Charles J Sande
Journal: The Lancet Healthy Longevity (2022)

Young infants and older adults are at greatest risk of life-threatening disease from respiratory syncytial virus (RSV) infection. Although hospitalisation data are sparse, estimates from the USA suggest that RSV is responsible for about 200 000 hospitalisations every year in older adults,1Matias G Taylor R Haguinet F Schuck-Paim C Lustig R Shinde V Estimates of hospitalization attributable to influenza and RSV in the US during 1997–2009, by age and risk status.BMC Public Health. 2017; 17: 271Crossref PubMed Scopus (61) Google Scholar and is associated with significantly worse clinical outcomes compared with influenza, including a significantly higher post-discharge mortality risk.2Ackerson B Tseng HF Sy LS et al.Severe morbidity and mortality associated with respiratory syncytial virus versus influenza infection in hospitalized older adults.Clin Infect Dis. 2019; 69: 197-203Crossref PubMed Scopus (72) Google ScholarThe mechanistic basis for severe disease risk in older adults is not well understood, although some studies have suggested that an age-related decline of immune function3Kelley WJ Zemans RL Goldstein DR Cellular senescence: friend or foe to respiratory viral infections?.Eur Respir J. 2020; 562002708Crossref PubMed Scopus (14) Google Scholar might underlie the increase in disease risk with age. A detailed understanding of the unique cellular and molecular risk factors that predispose older adults to severe disease is imperative in the design of interventions to reduce the burden of disease. The difficulty in developing a more complete understanding of the mechanisms of severe disease in older adults stems from the fact that almost all mechanistic studies to date have been hospital-based and have relied on samples collected at admission or shortly thereafter. Samples collected late in the infection course or that accompany the peak of symptoms provide little insight on the antecedent, preinfection factors that most probably play a role in directing the clinical course of disease. Furthermore, in such studies, the effect of key infection parameters on clinical severity—–such as viral load—is difficult to quantify as these parameters are often in decline at the time of admission.4Lukens MV van de Pol AC Coenjaerts FEJ et al.A systemic neutrophil response precedes robust CD8(+) T-cell activation during natural respiratory syncytial virus infection in infants.J Virol. 2010; 84: 2374-2383Crossref PubMed Scopus (99) Google Scholar Due to these limitations, controlled human infection studies have been used as an alternative study design to dissect the host–virus interaction over the entire infection course. Controlled infection studies provide a unique opportunity to examine, in detail, the early phases of infection before the escalation of clinical symptoms, and to examine how baseline variables such antibody concentrations modify infection risk and clinical outcomes.Controlled human infection with RSV was pioneered in the 1960s with studies that were designed to examine correlates of immunity,5Mills 5th, J Van Kirk JE Wright PF Chanock RM Experimental respiratory syncytial virus infection of adults. Possible mechanisms of resistance to infection and illness.J Immunol. 1971; 107: 123-130PubMed Google Scholar and it extended to the 1980s with studies that sought to investigate optimal routes of inoculation,6Hall CB Douglas Jr, RG Schnabel KC Geiman JM Infectivity of respiratory syncytial virus by various routes of inoculation.Infect Immun. 1981; 33: 779-783Crossref PubMed Scopus (0) Google Scholar and to the 1990s when these models were used to study the duration of immunity.7Hall CB Walsh EE Long CE Schnabel KC Immunity to and frequency of reinfection with respiratory syncytial virus.J Infect Dis. 1991; 163: 693-698Crossref PubMed Scopus (562) Google Scholar More recently, controlled RSV infection studies have been used to test the efficacy of small molecule antivirals in suppressing viral load8DeVincenzo JP Whitley RJ Mackman RL et al.Oral GS-5806 activity in a respiratory syncytial virus challenge study.N Engl J Med. 2014; 371: 711-722Crossref PubMed Scopus (251) Google Scholar and have also been used in phase 2b vaccine trials to provide preliminary evidence of vaccine efficacy against clinical and virological endpoints in adults who are experimentally infected after vaccination. RSV controlled infection studies have also been used to examine patterns of pathology in the lower airway after infection.9Jozwik A Habibi MS Paras A et al.RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection.Nat Commun. 2015; 610224Crossref PubMed Scopus (167) Google ScholarA common feature of all controlled RSV infection studies done over the past 60 years is that they have been conducted in young healthy adults with no underlying comorbidities. Although these studies have been invaluable in advancing our understanding of the early kinetics of infection, the study populations were not at significant risk of serious disease. There have been longstanding concerns over whether cellular, immunological, or virological insights derived from controlled infection of young healthy adults can be feasibly extrapolated to frail, older individuals with serious comorbid conditions.The ground-breaking study by Stephanie Ascough and colleagues10Ascough S Dayananda P Kalyan M et al.Divergent age-related humoral correlates of protection against respiratory syncytial virus infection in older and young adults: a pilot, controlled, human infection challenge model.Lancet Healthy Longevity. 2022; 3: e405-e416Summary Full Text Full Text PDF Scopus (1) Google Scholar is, to our knowledge, the first effort to address this question by conducting a controlled human infection study of RSV in older adults. Ascough and colleagues experimentally infected 12 older individuals aged 60–75 years with the Memphis-37 strain of RSV, and examined attack rates, viral load, and immune response over the course of infection. These parameters were also measured in a comparison cohort of 21 adults aged 18–55 years, who had been infected with the same strain. The results of the study are striking: no differences were found in the level of post-challenge antibody secreting cells specific to viral proteins, neutralising antibody, or binding antibodies targeting the virus fusion protein between these groups. However, the authors found that, unlike in the younger cohort, serum IgG was associated with resistance from infection among older adults, suggesting that these antibodies are a strong immune correlate of protection in older adults. In summary, the study by Ascough and colleagues represents a leap in the quest to understand severe RSV disease in adults. It describes a controlled human infection model for older adults that can be harnessed as a tool to examine the many facets of this complex disease, ranging from mechanistic studies of severe disease to early clinical trials of antivirals and vaccines targeted at the older adult population. Young infants and older adults are at greatest risk of life-threatening disease from respiratory syncytial virus (RSV) infection. Although hospitalisation data are sparse, estimates from the USA suggest that RSV is responsible for about 200 000 hospitalisations every year in older adults,1Matias G Taylor R Haguinet F Schuck-Paim C Lustig R Shinde V Estimates of hospitalization attributable to influenza and RSV in the US during 1997–2009, by age and risk status.BMC Public Health. 2017; 17: 271Crossref PubMed Scopus (61) Google Scholar and is associated with significantly worse clinical outcomes compared with influenza, including a significantly higher post-discharge mortality risk.2Ackerson B Tseng HF Sy LS et al.Severe morbidity and mortality associated with respiratory syncytial virus versus influenza infection in hospitalized older adults.Clin Infect Dis. 2019; 69: 197-203Crossref PubMed Scopus (72) Google Scholar The mechanistic basis for severe disease risk in older adults is not well understood, although some studies have suggested that an age-related decline of immune function3Kelley WJ Zemans RL Goldstein DR Cellular senescence: friend or foe to respiratory viral infections?.Eur Respir J. 2020; 562002708Crossref PubMed Scopus (14) Google Scholar might underlie the increase in disease risk with age. A detailed understanding of the unique cellular and molecular risk factors that predispose older adults to severe disease is imperative in the design of interventions to reduce the burden of disease. The difficulty in developing a more complete understanding of the mechanisms of severe disease in older adults stems from the fact that almost all mechanistic studies to date have been hospital-based and have relied on samples collected at admission or shortly thereafter. Samples collected late in the infection course or that accompany the peak of symptoms provide little insight on the antecedent, preinfection factors that most probably play a role in directing the clinical course of disease. Furthermore, in such studies, the effect of key infection parameters on clinical severity—–such as viral load—is difficult to quantify as these parameters are often in decline at the time of admission.4Lukens MV van de Pol AC Coenjaerts FEJ et al.A systemic neutrophil response precedes robust CD8(+) T-cell activation during natural respiratory syncytial virus infection in infants.J Virol. 2010; 84: 2374-2383Crossref PubMed Scopus (99) Google Scholar Due to these limitations, controlled human infection studies have been used as an alternative study design to dissect the host–virus interaction over the entire infection course. Controlled infection studies provide a unique opportunity to examine, in detail, the early phases of infection before the escalation of clinical symptoms, and to examine how baseline variables such antibody concentrations modify infection risk and clinical outcomes. Controlled human infection with RSV was pioneered in the 1960s with studies that were designed to examine correlates of immunity,5Mills 5th, J Van Kirk JE Wright PF Chanock RM Experimental respiratory syncytial virus infection of adults. Possible mechanisms of resistance to infection and illness.J Immunol. 1971; 107: 123-130PubMed Google Scholar and it extended to the 1980s with studies that sought to investigate optimal routes of inoculation,6Hall CB Douglas Jr, RG Schnabel KC Geiman JM Infectivity of respiratory syncytial virus by various routes of inoculation.Infect Immun. 1981; 33: 779-783Crossref PubMed Scopus (0) Google Scholar and to the 1990s when these models were used to study the duration of immunity.7Hall CB Walsh EE Long CE Schnabel KC Immunity to and frequency of reinfection with respiratory syncytial virus.J Infect Dis. 1991; 163: 693-698Crossref PubMed Scopus (562) Google Scholar More recently, controlled RSV infection studies have been used to test the efficacy of small molecule antivirals in suppressing viral load8DeVincenzo JP Whitley RJ Mackman RL et al.Oral GS-5806 activity in a respiratory syncytial virus challenge study.N Engl J Med. 2014; 371: 711-722Crossref PubMed Scopus (251) Google Scholar and have also been used in phase 2b vaccine trials to provide preliminary evidence of vaccine efficacy against clinical and virological endpoints in adults who are experimentally infected after vaccination. RSV controlled infection studies have also been used to examine patterns of pathology in the lower airway after infection.9Jozwik A Habibi MS Paras A et al.RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection.Nat Commun. 2015; 610224Crossref PubMed Scopus (167) Google Scholar A common feature of all controlled RSV infection studies done over the past 60 years is that they have been conducted in young healthy adults with no underlying comorbidities. Although these studies have been invaluable in advancing our understanding of the early kinetics of infection, the study populations were not at significant risk of serious disease. There have been longstanding concerns over whether cellular, immunological, or virological insights derived from controlled infection of young healthy adults can be feasibly extrapolated to frail, older individuals with serious comorbid conditions. The ground-breaking study by Stephanie Ascough and colleagues10Ascough S Dayananda P Kalyan M et al.Divergent age-related humoral correlates of protection against respiratory syncytial virus infection in older and young adults: a pilot, controlled, human infection challenge model.Lancet Healthy Longevity. 2022; 3: e405-e416Summary Full Text Full Text PDF Scopus (1) Google Scholar is, to our knowledge, the first effort to address this question by conducting a controlled human infection study of RSV in older adults. Ascough and colleagues experimentally infected 12 older individuals aged 60–75 years with the Memphis-37 strain of RSV, and examined attack rates, viral load, and immune response over the course of infection. These parameters were also measured in a comparison cohort of 21 adults aged 18–55 years, who had been infected with the same strain. The results of the study are striking: no differences were found in the level of post-challenge antibody secreting cells specific to viral proteins, neutralising antibody, or binding antibodies targeting the virus fusion protein between these groups. However, the authors found that, unlike in the younger cohort, serum IgG was associated with resistance from infection among older adults, suggesting that these antibodies are a strong immune correlate of protection in older adults. In summary, the study by Ascough and colleagues represents a leap in the quest to understand severe RSV disease in adults. It describes a controlled human infection model for older adults that can be harnessed as a tool to examine the many facets of this complex disease, ranging from mechanistic studies of severe disease to early clinical trials of antivirals and vaccines targeted at the older adult population. I declare no competing interests. Divergent age-related humoral correlates of protection against respiratory syncytial virus infection in older and young adults: a pilot, controlled, human infection challenge modelBetter understanding of age-related differences in clinical outcomes and immune correlates of protection can overcome reduction in vaccine efficacy with advancing age. We identify correlates of protection in older adults, revealing previously unrecognised factors which might have implications for targeted vaccine discovery and drug development in this vulnerable group. Full-Text PDF Open Access